Monheit Law sent a Freedom of Information Act (FOIA) request to the FDA on April 30, 2015. We requested all the adverse event reports involving Zofran or its active ingredient ondansetron.

“Adverse event reports” are just that – reports of unfavorable health outcomes that physicians believe to be linked to a pharmaceutical product. Doctors are allowed to submit reports of adverse events to the US Food & Drug Administration’s Adverse Event Reporting System. When drug manufacturers receive such reports, they are required to submit them to the FDA. The FDA compiles a database, and uses the information to identify new potential risks associated with a drug.

Eventually, we received two data files, stretching from January 1, 1991 to April 30, 2015. The files contained more than 3,800 pages, and included a total of 8,682 individual adverse event reports. We scoured the data, searching for any adverse event reports involving prenatal exposure to Zofran. Then we compiled a list of every adverse fetal event, from birth defects to spontaneous abortions, associated with Zofran.

Here are the results:

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Monheit Law’s Zofran Birth Defect FOIA Request: A Detailed Look

We found a total of 475 individual adverse event reports (AER) in which fetal exposure to Zofran, or its active ingredient, was linked to an adverse fetal outcome or congenital anomaly (birth defect).

Note that the FDA sent us 8,682 adverse event reports in response to our FOIA request. 475 represents around 5.4% of the total.

Out of those 475 AERs, 21 contained references simply to “congenital anomaly,” without any more specification.

Below, you’ll find a detailed review of the specific congenital abnormalities for which Zofran was a suspected cause. We’ve chosen to break the adverse events down by physiological region, and provided reference numbers so you can look up specific AERs in the FDA data files we received, which are linked below. You can find more information on how to interpret our numbers and AERs in general here.

“Cardiac septal defects,” or “hole in the heart” defects, involve cardiac walls that have failed to form properly during early fetal development. Rather than being contained by a continuous surface, blood is allowed to flow from one side of the heart to the other through a perforation.

See: 754

16 references to “atrial septal defect”

A type of cardiac septal defect, atrial septal defect occurs when a hole remains in the wall that would normally separate the heart’s two upper chambers, the atria.

This congenital defect occurs when veins that transport blood from the lungs attach to the heart at abnormal locations.

See: 645

3 references to “pulmonary valve stenosis”

A deformity that restricts blood flow from the heart to the lungs, generally caused by a valve that is thicker than normal or fails to open properly. “Stenosis” means “abnormally narrow.” We’ll see that term come up again.

See: 167, 2101, 2123

2 references to “pulmonary artery stenosis”

Similar to pulmonary valve stenosis, except that the abnormal narrowing is present in the pulmonary artery, a blood vessel leading from the heart to the lungs.

See: 1692, 2011

1 reference to “arterial stenosis”

An abnormal narrowing present in an artery. Arteries carry blood away from the heart; while vessels transport blood from the body back to the heart.

See: 3114*

1 reference to “pulmonary artery atresia”

“Atresia” occurs when a passageway in the body is abnormally closed or absent. In most forms of “pulmonary atresia,” a continuous sheet of tissue forms in the place where the pulmonary valve would normally be.

See: 712*

2 references to “pulmonary hypertension”

Hypertension, or high blood pressure, affecting the heart’s right side and arteries in the lungs. Pulmonary hypertension is often a long-term symptom of other congenital heart defects, although one of these reports (2,366*) listed the patient as an 87-day-old baby.

See: 1621, 2366*

2 references to “hypertension neonatal”

Abnormally high blood pressure.

See: 2000*, 3021*

2 references to “patent ductus arteriosus”

The ductus arteriosus is a blood vessel that allows blood to circumvent the lungs while baby’s are in the womb, since their oxygen source comes from maternal blood. After birth, the vessel usually closes after several days. In children born with patent ductus arteriosus, the vessel did not close.

See: 1621, 2366*

2 references to “left ventricular hypertrophy”

Thickening and enlargement of walls in the heart’s left ventricle.

See: 1518, 1665

2 references to “ventricular hypoplasia”

More commonly known as “hypoplastic left heart syndrome,” ventricular hypoplasia occurs when the heart’s left ventricle is severely underdeveloped. In many cases, the condition is fatal.

See: 712*, 1007*

3 references to “coarctation of the aorta”

The aorta, a large blood vessel that transports blood from the heart to the rest of the body, is abnormally narrow.

See: 2101, 2366*, 3569*

1 reference to “bicuspid aortic valve”

The aortic valve, which lies between the heart and the aorta, normally has three flaps, or “leaflets.” In this condition, the valve only has two flaps and can’t open properly.

See: 686*

2 references to “congenital aortic valve incompetence”

Defect in the aortic valve that allows blood to leak back into the left ventricle after being pumped into the aorta.

See: 2366*, 3569*

2 references to “congenital tricuspid valve atresia”

In healthy human hearts, blood flow between the right ventricle and atrium is controlled by the tricuspid valve. Babies born with tricuspid valve atresia don’t have that valve, but a solid sheet of tissue instead.

See: 1271*, 1342*

2 references to “Tetralogy of Fallot”

Four congenital heart defects that often occur together: ventricular septal defect, pulmonary stenosis, right ventricular hypertrophy and an overriding aorta, in which the aortic valve is enlarged.

See: 2101, 738*

1 reference to “mitral valve disease”

The mitral valve is located between the left ventricle and atrium, controlling blood flow between the two chambers.

See: 2366*

2 references to “Shone’s complex”

Four defects on the heart’s left side that occur together: coarctation of the aorta, subaortic stenosis, parachute mitral valve (a disorder that impairs the mitral valve’s ability to function) and supravalvular mitral membrance (an abnormal ring of tissue surrounding the mitral valve).

See: 2366*

1 reference to “dextrocardia”

The heart points toward the body’s right side, rather than to its left as is normal.

See: 686*

1 reference to “Wolff-Parkinson-White syndrome”

An extra electrical pathway leading between the atria and ventricles, often resulting in tachycardia, an abnormally fast heart beat.

See: 686*

1 reference to “arterial thrombosis”

A blood clot in an artery.

See: 865*

4 references to “cardiac flutter”

Also known as “atrial flutter”; an abnormal heart rhythm that begins in the heart’s atria.

See: 1165*, 1181*, 2091*, 2948*

6 references to “cardiac murmur”

An abnormal sound of blood flowing improperly through the heart; often a sign of an underlying cardiac septal defect.

See: 1186, 1715, 3114*, 3393*, 3569*, 3718*

2 references to “fetal arrythmia”

An abnormal heart rhythm. This is a general category that includes many specific rhythm anomalies.

See: 1765*, 3408*

1 reference to “persistent fetal circulation”

Blood flows through a baby’s body differently before birth. This condition occurs when the body fails to change from the circulation patterns before birth to those that normally develop shortly after birth.

See: 1621

1 reference to “peripheral venous disease”

This anomaly involves defects that prevent blood from flowing from the hands and feet to the heart properly.

“Haemoglobin,” or “hemoglobin” is a protein that allows red blood cells to carry oxygen.

See: 1812*

2 references to “haemoglobin decreased”

See: 2390*, 2859*

1 reference to “blood potassium increased”

Potassium is both a mineral and an electrolyte, that helps maintain the amount of water inside and outside of cells.

See: 1812*

1 reference to “blood potassium decreased”

See: 2015

1 reference to “haematocrit decreased”

“Haematocrit,” or “hematocrit” is the volume percentage of red blood cells in blood.

See: 2390*

1 reference to “naevus flammeus”

A birthmark caused by abnormally stretched capillaries.

See: 3635*

7 references to “haemangioma”

A type of birth mark that often appears red and rubbery, caused by the excessive growth of cells lining arteries and veins.

See: 3284*, 3287*, 3288*, 3289*, 3291*, 3300*, 3616*

Congenital Craniofacial Defects & Disorders

52 total references

7 references to “cleft lip and palate”

In 2012, a team of researchers at Harvard and Boston Universities found that babies exposed to Zofran in utero were 2.37 times more likely to be born with a cleft palate. To learn more about that study and orofacial clefts in general, click here.

See: 1711, 2100, 3343*, 3345*, 3393*, 3417*, 3417*

4 references to “cleft palate”

A split or opening in the roof of the mouth.

See: 1259, 3002*, 3013*, 3383*

2 references to “cleft uvula”

The uvula, the teardrop of flesh hanging above the opening to the throat, is “forked” or split.

See: 3013*, 3718*

3 references to “ankyloglossia congenital”

Tongue is “tethered” to floor of mouth by abnormally long strip of tissue.

See: 1186, 1895, 1033*

3 references to “Pierre Robin syndrome”

A sequence of congenital anomalies that occur together, including cleft palate; “micrognathia,” an abnormally small lower jaw; “retrognathia,” a jaw that is set back; and “glossoptosis,” a tongue that falls back in the throat, obstructing the upper airway.

See: 1032, 1259, 3002*

2 references to “micrognathia”

Abnormally small lower jaw.

See: 1259, 934*

1 reference to “retrognathia”

lower jaw is set further back than normal in relation to the face’s skeletal features.

See: 1259

1 reference to “glossoptosis”

Abnormal retraction of the tongue.

See: 1259

1 reference to “upper airway obstruction”

See: 1259

2 references to an unspecified “congenital nose malformation” or “deformity”

See: 934*, 3389*

3 references to an unspecified “ear malformation”

See: 2123, 718*, 934*

5 references to “deafness congenital”

See: 725*, 795*, 3114*, 3343*, 3345*

3 references to “otitis media chronic”

Chronic middle ear infections; often a symptom of cleft palate.

See: 1711, 3343*, 3345*

1 reference to “otitis media acute”

Acute middle ear infection.

See: 3284*

3 references to “eustachian tube dysfunction”

The eustachian tube links the middle ear to the cavity above the roof of the mouth.

See: 3284*, 3343*, 3345*

1 reference to “low set ears”

Ears are positioned on the head lower than is normal.

See: 3114*

1 reference to an unspecified “skull malformation”

See: 3284*

1 reference to “craniosynostosis”

Joints between skull bones fuse prematurely.

See: 3538*

1 reference to an unspecified “congenital jaw malformation”

See: 3649*

2 references to an unspecified “speech disorder”

In one of these reports (1767*), the affected patient is listed as a two-year-old. On page 3114*, the patient’s age is not listed, but the condition is referred to as “speech disorder developmental.”

Breakage of the amniotic sac more than an hour before the onset of labor.

See: 201, 941*, 1591*, 3256*

1 reference to “artificial rupture of membranes”

Performed to accelerate labor.

See: 3117*

1 reference to “amniorrhea”

Leaking amniotic fluid.

See: 2390*

1 reference to “amniocentesis abnormal”

“Amniocentesis” is a prenatal medical procedure in which physicians extract a sample of amniotic fluid and test the substance for signs of genetic anomalies and infection. Amniocentesis is generally performed between the 16th and 20th weeks of pregnancy.

See: 811*

2 references to “pre-eclampsia”

Pregnancy complication, generally beginning after the 20th week of pregnancy, characterized by elevated blood pressure and symptoms of organ damage, usually to the kidneys.

See: 3123*, 3549*

1 reference to “premature separation of placenta”

Or “placental abruption”; placental lining separates from uterus before delivery.

See: 1660

4 references to “oligohydramnios”

Deficient amount of amniotic fluid surrounding baby in womb.

See: 1211, 1519, 1666, 762*

3 references to an unspecified “umbilical cord abnormality”

See: 1790, 865*, 1617*

1 reference to “umbilical cord around neck”

See: 2952*

3 references to an unspecified “placental disorder”

See: 273, 546*, 1260*

3 references to “placental transfusion syndrome”

A disease affecting identical twin pregnancies; a shared placenta with abnormal blood vessels connects the circulatory systems and umbilical cords of the twins.

See: 1270*, 1271*, 1342*

1 reference to “placental insufficiency”

Placenta is unable to deliver adequate amounts of oxygen and nutrients to developing baby.

See: 1790

1 reference to “placenta praevia”

Placenta blocks the uterus, inhibiting delivery.

See: 2859*

1 reference to “placenta praevia haemorrhage”

A case of placenta praevia in which bleeding occurs.

See: 2849*

6 references to “haemorrhage”

See: 370, 546*, 980*, 1165*, 1171*, 1591*

63 references to “fetal growth restriction” or “growth retardation”

Various definitions for “fetal growth restriction” have been proposed: fetal weight below the 10th percentile for gestational age is most common.

“Apgar” (for Appearance, Pulse, Grimace, Activity, Respiration) is a test given to newborns directly after birth; a quick evaluation of a baby’s physical health.

See: 471, 583, 643, 702*, 702*, 811*, 1398*, 1695*

5 references to “developmental delay”

According to the University of Michigan Health System, “child development refers to how a child becomes able to do more complex things as they get older.” Thus a “developmental delay” can be considered a delay in this process. Developmental delays can pertain to motor, language, social or cognitive skills.

See: 725*, 1342*, 3114*, 3284*, 3543*

1 reference to “failure to thrive”

Insufficient weight gain of a newborn.

See: 3114*

1 reference to “lipoatrophy”

A localized loss or absence of fat tissue.

See: 3649*

1 reference to “systemic mastocytosis”

Levels of mast cells, a type of cell in the immune system, abnormally high in several organs.

See: 1791

1 reference to “mastocytoma”

A type of tumor consisting of mast cells.

See: 3635*

1 reference to “cystic lymphangioma”

Lesions or cysts in the lymphatic system.

See: 3889*

A Note On Our Numbers

The numbers listed above represent the total number of references a particular birth defect received in the adverse event reports Monheit Law was sent by the FDA. Many individual Adverse Event Reports list multiple separate birth defects. Further, where symptoms of a particular defect were listed alongside the abnormality, we counted only the defect itself.

Because one adverse event report may list multiple congenital anomalies, the number of specific conditions referenced in our list won’t correspond to the 475 total adverse fetal event reports provided by the FDA. Nor do the numbers presented here represent the true number of birth defect and adverse fetal events that may in fact be linked to prenatal exposure to Zofran.

Duplicate page numbers are not an error. Where numbers are repeated, a single page presented more than one adverse event report listing the same adverse fetal event.

Interpreting Adverse Event Reports

The broader level (referred to as “Outcome” in our FOIA reports) is a series of two-letter designations, like DE (for “Death”) or “LT” (for “Life-threatening”). These designations generally correspond to the severity of an adverse event or its repercussions, rather than the specific medical nature or diagnosis of the outcome being reported. Those more specific diagnoses are listed under the heading “Preferred Term.”

With that being said, one of the two-letter designations is “CA,” representing “Congenital Anomaly.” Unfortunately, the reporting of adverse events is far from rigorous. Many reports are incomplete and lack critical data. In our own experience, there were numerous AERs that clearly pertained to birth defects, or “congenital anomalies,” but had not been labeled “CA.” Many of these reports were instead classified as “OT,” for “Other.”

Here’s an example (from page 361):

Under “Outcomes,” our high-level classification, we find “OT,” representing “Other.” But under “Preferred Term,” where specific diagnoses and symptoms are listed, we find “microcephaly.” Microcephaly is a congenital anomaly, a birth defect, but obviously this report hasn’t been labeled “CA.”

Under “Case Type,” we find “Expedited.” Only reports that have been submitted directly by pharmaceutical manufacturers are labeled “Expedited.” Reports submitted by health care professionals are labeled “Direct.”

Sometimes, it’s easy to tell which manufacturer submitted a report. It’s not visible in the image above, but each AER has another field labeled “Manufacturer Control #.” Reports submitted by GlaxoSmithKline generally have a control number like the one to the right.

In referring to these data files, you may notice that we’ve changed the spelling of certain conditions. That’s because the FDA uses the Medical Dictionary for Regulatory Activities (MedDRA®), a standardized dictionary of medical terms. MedDRA uses many British spellings that aren’t as familiar to American readers, so we’ve altered them where appropriate.

Click on the buttons below to download the files we received in response to our FOIA request. Page numbers marked with an asterisk (*) refer to the first file, while unmarked page numbers can be found in the second.

Do Adverse Event Reports Present A Complete Picture?

No. In fact, many sources, including the US Food & Drug Administration, have stated that adverse event reporting in the United States is woefully inadequate.

According to QuarterWatch, a publication of the Institute for Safe Medication Practices that uses Adverse Event Report data to independently highlight potential safety issues, “both the FDA and QuarterWatch […] report[…] that the number of [adverse event] reports in children [are] too few for effective postmarket surveillance. For birth defects, reporting is even more limited, compounded by poor quality reporting.”

In other words, adverse event reporting in relation to birth defects is so infrequent, and of such poor quality, that the FDA’s Adverse Event Reporting System can’t even do what it was designed to: help regulators evaluate emerging safety risks from previously-approved pharmaceutical products.

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